The present invention relates to methods of modulating nicotinic receptors by use of analogs of galanthamine and lycorarmine. Modulation of such receptors is useful in improving attentional functions, relieving pain, treating nicotine and similar addictions, treating anxiety and depression, treating and retarding the progression of Alzheimer""s and Parkinson""s diseases, neuroprotection against neurodegenerative disorders, alcohol, glutamate and other toxic effects and treatment of schizophrenia.
Galanthamine is an alkaloid isolated initially from galanthus nivalis, the snowdrop, which has been used for many years as an acetyleholinesterase inhibitor. The principal use in humans has been the postoperative reversal of neuromuscular blockade. It has also been administered in number of neuromuscular diseases. Because of the activation of muscle, it was of interest to determine the relationship between galanthamine""s anticholinesterase activity and its ability to induce twitch potentiation in muscle.
In intact cats, twitch potentiation of the gastrocnemius by direct electric stimulation was measured after intravenous infusion of neostigmine, physostigmine and galanthamine. (Ueda M, Matsumura S, Kimoto S, Matsuda S, Studies on the anticholinesterase and twitch potentiation activities of galanthamine. Jap J Pharmacol 12:111-119, 1962) Galanthamine was 1/10.5xc3x97 as active as neostigmine and 1/3.5xc3x97 as active as physostigmine. (p 114) The IC 50 for cholinesterase inhibition, measured in rat brain, erythrocytes, or gastrocnemius homogenate, is in the range of 200 times lower for neostigmine, and 50 times lower for physostigmine than for galanthamine. (Table 4, p 115) This produced a disproportion between the magnitude of twitch potentiation and the enzymatic activity. The authors note
xe2x80x9cAlthough the anticholinesterase activity of galanthamine is far inferior to those of neostigmine and physostigmine, the twitch potentiation by galanthamine administration is only {fraction (1/10)} of that of neostigmine or physostigmine. So it is presumed that factors other than anticholinesterase activity are concerned with the twitch potentiating effects of galanthamine.xe2x80x9d
In their discussion, they review this point.
xe2x80x9cAlthough the anticholinesterase activity of galanthamine is about {fraction (1/100)} that of neostigmine or physostigmine, the twitch potentiating effects of galanthamine in the nerve muscle preparation is about {fraction (1/10)} of the latter. These contradictions between the twitch potentiation and anticholinesterase activity are also not solved by the direct effects of galanthamine on the muscle fibres or by the difference of species in the experimental animals.xe2x80x9d
The authors consider that the effects of galanthamine may not represent either anticholinesterase activity, or a direct effect, such as would be expected from a depolarizer. They cite the arguments of prior authors that the classical view of acetylcholine accumulation at the neuromuscular junction was inconsistent with xe2x80x9cthe following points; (1) Potent depolarizers do not necessarily show the marked twitch potentiation. (2) Twitch potentiations caused by anticholinesterase like neostigmine appeared soon after the administration of the compound.xe2x80x9d Thus, the enhancement of the activity of endogenous transmitter released by electrical stimulation was neither consistent with the time course or potency of anticholinesterases, nor could it be attributed to direct depolarization. Therefore, twitch potentiation was most likely attributable to an action on motor nerve terminals other than enzyme inhibition or direct agonism.
Motor nerve terminals, i.e., the neuromuscular junction, functions by means of a nicotinic cholinergic recepter. Such receptors are found also in ganglia. Kostowski and Gomulka (Note on the ganglionic and central actions of galanthamine, Int J Neuropharmacol, 7:7-14, 1968) investigated the effects of galanthamine and physostigmine on ganglionic transmission in the cat. The drugs were administered intra-arterially and depolarization was recorded from the surface of the superior cervical ganglion. Physostigmine and galantamine were administered in comparable doses, 250 micrograms, which represent fairly equal molarity, as the molecular weight of physostigmine salicylate is 413 and that of galanthamine hydrobromide is 368. As noted above, this represents much greater anticholinesterase potency for physostigmine. As shown in FIG. 1A, p 9, galanthamine, but not physostigmine, substantially inhibited hexamethonium (C6) induced ganglionic blockade. Direct recordings are shown in FIG. 2, p 10, in which preservation of the surface potential is shown in galanthamine, but not physostigmine-treated ganglia. The authors considered that differential penetrability might contribute to these results, but that
xe2x80x9cthe differences in the direct actions of the drugs on ganglionic cholinoceptive sites should also be taken into consideration. In the superior cervical ganglion of the cat, two distinct excitatory cholinoceptive sites have been described . . . The first is activated by nicotine, tetramethylammonium (TMA) and inhibited by curare or hexamethonium-like drugs, whereas the second type is characterized by its sensitivity to muscarine and acetyl-b-methylcholine excitation and to blockade by atropine. Both types of cholinoceptive sites, muscarinic and nicotinic, can be activated by acetylcholine . . . The ability of galantamine to prevent the C6 induced ganglionic blockade suggests that this effect seems to be due to excitation of xe2x80x98nicotinic cholinoceptive sitesxe2x80x99. . . The increase in ganglionic surface potential in ganglia treated with galantamine also supports the hypothesis that such a mechanism is involved in the action of some anticholinesterases.xe2x80x9d
Recent observations are consistent with the mechanisms proposed by the early authors. Using clonal rat pheochromocytoma (PC12) cells, Storch et al confirmed the conclusions of Ueda more than thirty years earlier. (Storch A, Schrattenholz A, Cooper J C, Abdel Ghani E M, Gutbrod O, Weber K-H, Reinhardt S, Lobron C, Hermsen B, Soskic V, Periera E F R, Albuquerque E X, Methfessel C, Maelicke A, Physostigmine, galanthamine and codeine act as xe2x80x98noncompetitive nicotinic receptor agonistsxe2x80x99 on clonal rat pheochromocytoma cells. Eur J Pharmacol Mol Pharmacol Sect 290:207-219, 1995)
The authors note that xe2x80x9cphysostigmine, galanthamine and codeine do not evoke sizable whole-cell currents, which is due to the combined effects of low open-channel probability, slow onset and slow inactivation of response.xe2x80x9d These agents require an ion channel which has been opened, as can be done by a direct agonist, in order to have an effect. Physostigmine and galanthamine do, however, cause some channel activation in inside-out patches from PC 12 cells. This activation can also be produced by acetylcholine. Methyllycaconitine, a competitive nicotinic antagonist, blocks the activation by acetylcholine, but not by the cholinesterase inhibitors. (FIG. 2, p 211) Galanthamine and physostigmine are, therefore, not binding at the agonist site. On the other hand, after incubation with FK1, a competitive monoclonal antibody to physostigmine, neither physostigmine nor galanthamine could induce single channel activity, while acetylcholine still could. The authors conclude xe2x80x9cIn other words, (xe2x88x92)-physostigmine (and galanthamine) [that is the authors""s addition in parentheses] acted as noncompetitive agonists at nicotinic receptors of PC12 cells.xe2x80x9d (p213)
Thus, the ability of galanthamine to enhance activation of motor nerve terminals stimulated electrically, to increase ganglionic depolarization induced by acetylcholine and to protect against hexamethonium, indicating enhancement of the activity of nicotinic receptors, has been confirmed with the newer methods of patch-clamp and antibody techniques.
The present invention provides a method for modulating nicotinic by administering an effective amount of a galanthamine or lycoramine analog to a patient in need of such modulation.